Tivozanib for the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) represents a heterogeneous group of cancers with distinct histological features, molecular alterations, prognosis, and response to therapy. Target agents directed against vascular endothelial growth factor and its receptor and mammalian target of rapamycin (mTOR) inhibitors have completely changed the landscape of RCC. However, the rate of complete response is still low, thus supporting the research of novel therapeutic agents.

Area covered: The authors describe the chemical features of tivozanib, its pharmacodynamic and pharmacokinetic properties, and the results obtained in human phase I–III clinical trials. Tivozanib received its first global approval in EU, Iceland, and Norway on 28 August 2017 for the first-line treatment of adult patients with advanced RCC and for adult patients who are VEGFR and mTOR inhibitor-naive following disease progression after one prior treatment with cytokines.

Expert opinion: The US Food and Drug Administration did not approve tivozanib due to the lack of a significant advantage in terms of survival compared to sorafenib. To date, the role of tivozanib in the pharmaceutical landscape of mRCC appears to be very limited. However, ongoing trials on the association between tivozanib and immunotherapy may represent a promising strategy to be assessed in future clinical trials.     

From the Cover: Feature Article: Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors

Analyses of compounds in clinical development have shown that ligand efficient-molecules with privileged physical properties and low dose are less likely to fail in the various stages of clinical testing, have fewer postapproval withdrawals, and are less likely to receive black box safety warnings. However, detailed side-by-side examination of molecular interactions and properties within single drug classes are lacking. As a class, VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) have changed the landscape of how cancer is treated, particularly in clear cell renal cell carcinoma, which is molecularly linked to the VEGF signaling axis. Despite the clear role of the molecular target, member molecules of this validated drug class exhibit distinct clinical efficacy and safety profiles in comparable renal cell carcinoma clinical studies. The first head-to-head randomized phase III comparative study between active VEGFR TKIs has confirmed significant differences in clinical performance [Rini BI, et al. (2011) Lancet 378:193–1939]. To elucidate how fundamental drug potency–efficiency is achieved and impacts differentiation within the VEGFR TKI class, we determined potencies, time dependence, selectivities, and X-ray structures of the drug–kinase complexes using a VEGFR2 TK construct inclusive of the important juxtamembrane domain. Collectively, the studies elucidate unique drug–kinase interactions that are dependent on distinct juxtamembrane domain conformations, resulting in significant potency and ligand efficiency differences. The identified structural trends are consistent with in vitro measurements, which translate well to clinical performance, underscoring a principle that may be broadly applicable to prospective drug design for optimal in vivo performance.     

Progress and contrasts of the development of tivozanib for therapy of kidney cancer

Introduction: Targets for drug development for the treatment of kidney cancer (renal cell carcinoma; RCC) include vascular endothelial growth factor (VEGF) and its receptors and mammalian target of rapamycin. Currently available oral multitargeted VEGF tyrosine kinase inhibitors (TKIs) that have been approved by the US Food and Drug Administration for advanced RCC, include sunitinib, sorafenib and pazopanib. Off-target TKI inhibition can potentially preclude full-dose combination with other targeted and chemotherapeutic agents. There is a need to develop more potent and selective targeted agents for RCC therapy, which are more effective and have minimal off-target effects.

Areas covered: This drug evaluation review addresses the ongoing development for the treatment of RCC with tivozanib: a potent, selective and long-half-life VEGF TKI. The testing for clinical efficacy alone or in combination with other therapies for RCC and for other tumor types, and the clinical and market relevance of introducing another RCC therapy are discussed.

Expert opinion: Tivozanib is distinguished by its high potency, selectivity, long-half-life and its potential to be effectively combined with other agents in RCC. This may offer more effective, yet well-tolerated treatment options. The relative clinical and market relevance remain to be seen, both for RCC therapy and other tumor types.     

Tivozanib: current status and future directions in the treatment of solid tumors

Introduction: Tivozanib is a novel tyrosine kinase inhibitor (TKI) which inhibits vascular endothelial growth factor (VEGF) receptors-1, -2, and -3 at nanomolar concentrations.

Areas covered: A comprehensive MEDLINE and American Society of Clinical Oncology abstract search was performed to gather all relevant clinical and translational data related to tivozanib. We discuss pre-clinical studies associated with tivozanib, and the results of a Phase I assessment in advanced solid tumors. We highlight combination studies with tivozanib, including pairings of tivozanib with cytotoxic therapy in patients with colorectal cancer and breast cancer. A randomized discontinuation Phase II study and a randomized Phase III study assessing the activity of tivozanib in metastatic renal cell carcinoma (mRCC) are described in detail.

Expert opinion: Tivozanib will face the challenge of entering an already crowded therapeutic space in mRCC—emerging combination studies and biomarker assessments may distinguish this agent among other VEGF-TKIs. The current review will outline the development pathway of tivozanib to date, and offer lessons learned and future opportunities.     

Tivozanib的合成

3,4-二甲氧基苯胺(2)与乙氧基亚甲基丙二酸二乙酯经取代、环合、水解、脱羧及氯代反应制得4-氯-6,7-二甲氧基喹啉(6);或以2、米氏酸和原甲酸三甲酯为原料,经取代、环合、氯代反应制得6。6与4-氨基-3-氯苯酚盐酸盐(7)进行醚化反应后,再与3-氨基-5-甲基异噁唑进行成脲反应制得抗肿瘤药tivozanib,总收率约35%～37%(以2计)。     

The role of tivozanib in advanced renal cell carcinoma therapy

Introduction: The efficacy of VEGF-targeting therapies in clinical trials led to their recommendation in clinical guidelines for use across the advanced or metastatic renal cell carcinoma (RCC) treatment landscape, however, tolerability (including off-target effects) has remained a challenge. Tivozanib is a selective inhibitor of all three VEGFRs, with limited off-target interaction, which demonstrates efficacy with improved tolerability relative to multikinase VEGFR-TKIs.

Areas covered: Covered here is the clinical development of tivozanib in advanced RCC, including the pivotal Phase III, multicenter, open-label, randomized clinical study comparing tivozanib with sorafenib for the treatment of VEGF- and mTOR therapy-naïve advanced RCC patients. Also covered are ongoing trials, exploring the efficacy and safety of tivozanib in the setting of refractory disease and the utility of tivozanib in combination with checkpoint inhibitors for advanced RCC. Combination of a VEGFR-TKI and immunotherapy is promising in advanced RCC, if the treatment regimens have acceptable tolerability. Here the selectivity of tivozanib may contribute to an acceptable tolerability profile when used in combination therapy.

Expert commentary: The approval of tivozanib provides an additional option for the first-line treatment of advanced or metastatic RCC patients in Europe and allows use of a VEGFR-TKI with selectivity for VEGFRs in this setting.     

Thyroid dysfunctions induced by tyrosine kinase inhibitors

Introduction: Recently, tyrosine kinase inhibitors (TKIs) have emerged as a new class of anticancer therapy. Although generally considered less toxic than cytotoxic chemotherapy, TKIs do cause significant side effects including fatigue and hypertension. In addition, thyroid dysfunction is a well-known adverse effect of TKI.

Areas covered: This review provides a comprehensive assessment of TKI-induced thyroid dysfunctions by sunitinib, sorafenib, pazopanib, imatinib, dasatinib, nilotinib, vandetanib, axitinib, motesanib and tivozanib. Furthermore, the potential mechanisms that result in this toxicity, the clinical impact of thyroid dysfunction in these patients and the controversies regarding treatment with thyroid hormone (TH) therapy are evaluated.

Expert opinion: Detection of TKI-induced thyroid dysfunction requires routine monitoring of thyroid function and may necessitate treatment. Potential benefits in developing thyroid dysfunction and potential harm in treating it necessitate controlled studies. Finally, if treatment is pursued, appropriate dosing and timing of TH replacement will require prospective clinical evaluation.